Jonas Blomberg headed up a European group which produced an autoimmune model of ME/CFS

Blomberg has recently been immersed in a study designed to validate (or not) Dr. Scheibenbogen’s autoantibody findings in chronic fatigue syndrome (ME/CFS). The lead role the Europeans are taking on in exploring autoimmunity in ME/CFS is evident: Blomberg and Gottfries are Swedish, Scheibenbogen is German, and Mella and Fluge – of the Rituximab trial – are Norwegian.

(Carl-Gerhard Gottfries’ story is so unusual that it warrants a short retelling. Gottfries, a Swedish psychiatrist, recovered from ME/CFS using, of all things, a staphylococcus vaccine. Gottfries opened an ME/CFS clinic, published his findings and treated patients with the vaccine for several decades until it was withdrawn from the market. Find out more about Gottfries’ fascinating story here.)

There are so many ideas floating around concerning the cause ME/CFS that one is tempted to throw up one’s hands. Is cellular energy production in the dumps? Are the autonomic nervous system problems keeping people wired and exhausted at the same time? Is an autoimmune process pummeling the body? Are hidden infections tormenting ME/CFS patients with never ending flu-like symptoms? Or as Cortene suggests, are problems in the HPA axis wreaking havoc on the rest of the body.

The fact that so many people have proposed so many interesting hypotheses is encouraging, but the downside to such a munificence of possibilities is a kind of inertia. Until the ME/CFS field settles on one or a few models of disease, this small field is inevitably going to progress more slowly that we would wish.

In fact, the two Davises at Stanford (Ron and Mark – not related) have questioned whether the field should devote time and money to chasing down hypotheses at all. Better, they have suggested, to gather more and more data and see what emerges. That said, something has been emerging – an explanatory model in which autoimmunity plays a key role.

An Autoimmune Model of Chronic Fatigue Syndrome

Basically, the authors propose that it all starts with your genes and your leaky gut. Not the leaky gut you necessarily associate with ME/CFS but the leaky gut you had before, perhaps long before you came down with ME/CFS.

A Genetic Predisposition

Autoimmune diseases typically feature a strong genetic component and run in families. It’s not that rheumatoid arthritis shows up in family member after family member. It’s that a range of other autoimmune diseases do. Blomberg picks out three intriguing autoimmune diseases – thyroid disease, Sjogren’s Syndrome (SS) and lupus – which studies suggest run in ME/CFS families.

Evidence of a genetic predisposition is one of several factors suggesting ME/CFS could be an autoimmune disease.

ME/CFS itself is also associated with diseases Blomberg considers to be emerging autoimmune diseases including hypothyroidism, fibromyalgia and POTS, each of which has been associated with increased levels of autoantibodies. Blomberg clearly believes an autoimmune cluster containing many of the diseases associated with ME/CFS is emerging before our eyes.

High rates of two of those diseases (thyroid, SS) also recently showed up in a postural orthostatic tachycardia syndrome (POTS) study (along with antiphospholipid syndrome).

Blomberg then ploughed through genetic, immune and epigenetic data in ME/CFS, highlighting some findings suggesting autoimmunity might be present.

For instance, autoimmune diseases often occur when HLA molecules improperly display self-antigens to cytotoxic or helper T-cells. T-cells, it turns out, are often huge drivers of autoimmunity, and when they produce autoimmunity, HLA issues are often prominent. Guess what: an HLA issue has been found in ME/CFS. (Ron Davis is studying HLA genes in ME/CFS.) Another study found that increased prevalence of genetic alteration (a SNP) in a T-cell receptor gene known to play a role in autoimmunity suggested that a T-cell based autoimmune process could be present.

Infections, EBV, Autoimmunity and ME/CFS

Infections often trigger autoimmunity. In fact, the infectious trigger that has sparked ME/CFS for many is one big clue that an autoimmune process may be present. With regard to autoimmunity, the more severe the infection, the better, and several studies show that deficiencies in IgG subclasses may have left people with ME/CFS more vulnerable to a severe infection.

Several gene expression studies showing alterations in T-cell and innate immune response genes suggested that ME/CFS patients’ immune systems could be fighting off an infection.

The Autoimmune Virus

EBV is especially interesting as a facilitator of autoreactivity. Blomberg et. al.

If you’re unlucky enough to first meet up with the Epstein-Barr virus (a common trigger of ME/CFS) during adolescence, it’s likely to trigger your immune system to produce a massive number of antibodies, including autoantibodies. EBV also produces antigens with highly repetitive structures (e.g., Gly–Ala–Gly–Ala repeats in EBNA1) which tend to confuse the immune system and trigger the production of autoantibodies.

It’s no wonder, then, that infectious mononucleosis (glandular fever) significantly increases the risk of later coming down with at least two autoimmune diseases: multiple sclerosis (MS) and lupus. That’s an interesting enough intersection for Blomberg to assert that the immune responses that ME/CFS, MS and lupus have to EBV should be compared.

The Key Organ – the Gut

Anyone have gut symptoms (cramping, bloating, loose bowels, constipation) prior to ME/CFS? I did – they weren’t major, but if one area of my body was a little bit off back then, it was my gut.

Blomberg believes your leaky gut may be the key to your illness. Not the leaky gut you necessarily have now, but the leaky gut you had before you got ME/CFS.

Blomberg believes a genetic predisposition and a leaky gut set the stage for ME/CFS

The gut is such a potential hotspot for autoimmunity because it contains so much foreign material. In fact the gut has been posited as something of a training ground for the immune system- it provides the immune system with the foreign materials it needs to learn how to distinguish self from non-self.

Gut disturbances are fairly common in autoimmune diseases, and the idea that alterations in gut flora are touching off autoimmune processes is being examined in a host of autoimmune diseases (multiple sclerosis, type 1 diabetes, RA, ankylosing spondylitis). The common occurrence of irritable bowel syndrome (IBS) – and the leaky gut that often comes with it – in ME/CFS presents a potential pathway for autoimmunity.

Blomberg proposes that the breach of your gut barrier created a state of low level chronic inflammation prior to you getting ME/CFS. The gut barrier is important because it’s a place in the body where tolerance (the ability to distinguish between self and non-self antigens) is more difficult to maintain. Given the extraordinary diversity and sheer number of gut bacteria, it’s easy to see how the immune system could be overwhelmed and lose it’s way.

Blomberg believes that slow leakage from the gut created a population of auto-reactive B-cells that remained mostly inactive or quiescent (in a state of anergy), almost like undercover agents infiltrating a city, waiting for the signal to pounce. At some point a “decisive” immune event flipped them into action, and an autoimmune disease – ME/CFS – was born.

He bases his hypothesis of pathogenic autoantibody creation in ME/CFS on a process that appears to be occurring in lupus. The first step occurs when a genetically predisposed person meets up with bad gut bacteria. First, abnormal but not pathogenic B-cells, which have a “weak autospecificity”, appear. These weakly targeted B-cells are not strongly directed against a specific antigen or part of the cell and don’t appear to be particularly dangerous at first, but the body should still eliminate them. Blomberg proposes that it doesn’t.

Over time exposure to the bad gut bacteria causes the specificity of the B-cells to change – making them more targeted and dangerous. At some point an infection turns them on and they start producing clones of themselves which begin attacking the body. ME/CFS is born.

One possible sign that tolerance – the ability of the body to remove autoantibody-producing cells – has been breached in ME/CFS are the TFG-B (and IL-10) findings. IL-10 and TGF-B, in particular, are the rare cytokines that are more or less consistently found dysregulated in ME/CFS cytokine studies. It turns out that T-helper cells use both these cytokines to regulate tolerance and anergy at the gut mucosa – the very place Blomberg believes the process of autoimmunity in ME/CFS begins.

Ian Lipkin’s recent study found a significant difference in gut composition between ME/CFS patients with IBS and those without. Some of those differences appeared to affect energy production.

Autoantibodies

It turns out that autoantibodies by themselves are not necessarily indicative of autoimmunity. Some “natural autoantibodies – (mostly IgM antibodies) are simply designed to rid the body of dead/apoptotic, damaged and infected cells and rarely cause autoimmune diseases. Other more dangerous autoantibodies need to be turned on by “cell danger” signals before they do harm. (This is why autoantibodies can often be found in healthy people.)

Autoantibodies have, of course, been found in ME/CFS and related diseases like POTS. At the Montreal conference Blomberg reported that his team was validating Scheibenbogen’s autoantibody findings in ME/CFS. They are one clue that autoimmunity is happening in ME/CFS but they provide, Blomberg reported, only circumstantial evidence of autoimmunity.

It’s the “erroneously activated” B-cells, he reported, that are “the root of the evil”, and it’s these cells that need more focus. Blomberg asserts that an in-depth sequencing of these deranged B-cells is needed. By sequencing the variable immunoglobulin chains found in them it should be possible to trace back to how they turned bad.

Other Possible Evidence of Autoimmunity

As noted earlier, Carl-Gerhard Gottfries successfully used a staphylococcal vaccine for years to treat himself and others with chronic fatigue syndrome (ME/CFS). That approach may have worked because the immune stimulation it provoked may have been able to induce tolerance; i.e. induce the body to remove the bad B-cells.

Since Rituximab knocks down B-cells, thereby removing misbehaving ones, it would seem to fit into Blomberg’s hypothesis. Unfortunately, the Rituximab trial failed, and if anecdotal reports are correct, more completely than we could have imagined.

Another possible indication that autoimmunity is present in ME/CFS are studies suggesting the incidence of Hodgkin’s lymphoma is increased in ME/CFS as it is in other autoimmune diseases.

In the end, though, Blomberg reports that the evidence that autoimmunity is at work in ME/CFS is circumstantial. It relies on the fact that people with ME/CFS often have other autoimmune diseases such as thyroiditis or diseases suspected of involving autoimmunity such as POTS, FM and IBS, that autoantibodies are present, and that immunostimulation (IVIG, staphyloccocus vaccine) may work.

Most of the work, though, needed to fulfill the Witebsky–Rose criteria for autoimmunity, remains to be done.

At the start of their paper, Blomberg et. al. proposed that their model could explain many of the facets of ME/CFS that have emerged – the most prominent of which are the energy production problems.

An autoimmune disease exists in which an attack on the energy producing processes in the body produces symptoms and findings similar to those found in ME/CFS. In primary biliary cirrhosis (PBC) antibodies attack a small fatty acid molecule (lipoic acid) that’s part of the energy producing machinery on the surface of the mitochondria.

The antibodies in PBC attack the pyruvate dehydrogenase (PDH) enzyme complex which regulates the transition from glycolysis (anaerobic energy metabolism) to the tricarboxylic acid cycle (aerobic energy metabolism). The same issue -the transition from glycolysis to aerobic metabolism – has shown up repeatedly in ME/CFS studies.

Even though PBC is considered a liver disease, it produces enormous amounts of fatigue as well as cognitive problems, orthostatic intolerance and sympathetic nervous system hyperactivity. In fact, Julia Newton, who studied PBC before she studied ME/CFS and started a Rituximab trial in PBC two years ago, stated back in 2013 that,

“…at this stage the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC.”

Another fascinating aspect of PBC is that the autoantibodies are attacking a molecule, lipoic acid, which is added to the PDH enzyme using a rare process called lipoylation. Because some gut bacteria (Novosphingobium) also use lipoylation, it’s possible that bacterial leakage initiated the autoimmune process causing PBC.

Blomberg suggested that pathogenic, as yet unidentified immunoglobulins directed against mitochondrial proteins could be the source of ME/CFS and exhorted researchers to compare the post-exertional malaise in ME/CFS to other diseases such as fibromyalgia, PBC, etc.

Autoimmunity or Oxidative Stress?

Finally Blomberg et. al. suggested that oxidative stress could be producing the same energy depleting issues as autoimmunity. That’s an intriguing idea given the comforting consistency oxidative stress study results have had in ME/CFS. The authors noted that it was recently shown that the oxidation of a critical part of the pyruvate kinase enzyme can effectively block the transition of glycolysis to aerobic metabolism.

Dr. Shungu believes the lactate accumulations and glutathione reductions his studies have validated in the ventricles of the brains of ME/CFS patients are associated with oxidative stress.

Conclusion

Blomberg’s autoimmune model proposes that the seeds for ME/CFS were lain possibly long before the disease appeared and only “sprouted” once a decisive immune event occurred. He believes that a genetic predisposition plus a leaky gut laid the groundwork over time for what eventually became an autoimmune disease.

Autoantibodies provide circumstantial evidence of autoimmunity in ME/CFS but are not nearly enough to validate it. Blomberg asserted that an intensive study of the abnormal B-cells in ME/CFS could both help to validate that diagnosis and identify the precipitating event which triggered this illness.

If ME/CFS is an autoimmune disease targeting the mitochondria it may have a close cousin called primary biliary cirrhosis (PBC) which produces similar symptoms including enormous fatigue. In PBC autoantibodies disrupt the transition from anaerobic to aerobic energy production – the same process, interestingly enough, that appears to be affected in ME/CFS.

While autoimmune processes could produce the energy problems in ME/CFS, oxidative stress – which studies have found to be consistently high in this disease – could produce the same result.

Epigenetics research holds the fascinating possibility of figuring out what shifted at the very beginning of chronic fatigue syndrome (ME/CFS). For many with ME/CFS a sudden change occurred – some sort of biological reset quickly happened – which never relinquished itself.

Something triggered ME/CFS. Could it have been an epigenetic reset?

Finding out what “reset” occurred is what epigenetics is all about. Epigenetics identifies changes in the expression of our genes that occur after we meetup with biological stressors such as pathogens, drug, toxin or even foods.

Most of our genes that produce proinflammatory cytokines, for instance, have a kind of a lock on them. Removing that lock leaves them free to express themselves and leaves us open to poor health.

Epigenetics explores how the biological challenges we encounter in life can remove those locks (or add to them) resulting in an entirely new genetic landscape – one that could perhaps cause something like ME/CFS.

Many people’s ME/CFS/FM starts with an infection, and viruses can exert major epigenetic changes to our genome. Herpes simplex virus (the virus Dr. Pridgen is targeting in fibromyalgia) engineers changes to our genome which help the virus avoid destruction and enhance its replication. Those changes include a suppression of our immune system, which can result in an increased risk of cancer.

What goes around comes around, though. Epigenetic News recently reported that an epigenetic modifying cancer drug was able to return the parts of the immune system that the herpes simplex virus had disturbed to normal. The drug was able to effectively fill in the immune hole created by the herpes virus by boosting a number of immune factors (IFN-a, IL-8, IL-6, transcription factors, stress response factors). Mouse studies revealed that the drug also reduced reactivation of the virus.

That suggests that some similar drugs now in clinical trials could help in the fight against herpes and other viruses or could perhaps simply return to normal epigenetically modified genes that have suppressed immune functioning.

“A new class of antivirals based on this study might be useful for patients who are resistant to existing antivirals like acyclovir and ganciclovir….. (or in) viral infections for which there aren’t pharmaceuticals to boost an individual’s immune response.” Dr Kristie

If epigenetics turns out to play the major role in ME/CFS that it does in cancer and other diseases, a cancer drug could someday be in store for ME/CFS treatment.

Epigenetics Study Highlights Immune Alterations in ME/CFS

The epigenetics story begins with gene transcription – the first step in the process of translating our genes into proteins. Gene expression gets enabled by the removal of methyl groups that block transcription and/or by the addition of methyl groups that stop genes from being expressed.

Just a few epigenetic studies have been done in ME/CFS and none like this one. For one, the group took advantage of a new breakthrough in genetic testing (an advanced Illumina array) to almost double the number of testing sites (from 450,000 to 850,000 sites). For another, the larger sample size (64 participants from two geographically distant locations) ensured a more comprehensive look at the epigenetic changes in ME/CFS. This allowed the group to produce what they called “consensus hypomethylated sites” they believe could be used in future studies.

The general findings of the study agreed with those from past ME/CFS epigenetic studies. Hypomethylation – the deletion of methyl groups, which make it easier for the genes to be expressed – was the theme, with 98% of differentially methylated sites in ME/CFS hypomethylated compared to controls. (Only 2% were hypermethylated compared to controls.) The hypomethylation was most prominent in genes associated with immune cell regulation.

The high degree of hypomethylation was intriguing for several reasons. For one, Epstein-Barr Virus – presumably a common trigger in ME/CFS – overwhelmingly triggers hypomethylation and almost no hypermethylation of genes. Hypomethylation is also associated with pro-inflammatory gene expression in autoimmune diseases as well as in cancer promotion.

Multiple Sclerosis Breakthrough

A “global” hypomethylation, for instance, is also found in lupus and rheumatoid arthritis. The hypomethylation of a promoter gene for IL-6 in rheumatoid arthritis causes an overexpression of pro-inflammatory cytokines and other immune factors which ultimately results in joint damage.

The recently uncovered hypomethylation of an HLA gene in multiple sclerosis (MS) prompted researchers to state that epigenetic changes may even be “caus(ing) the disease”. That bold statement reflected the findings of a recent large study, which indicated that epigenetic changes were directly causing the largest risk factor found yet for MS.

That finding may have implications that go far beyond MS and could conceivably reach ME/CFS/FM. Since the HLA region of the genome is associated with almost all autoimmune diseases, the authors believe their finding will impact other autoimmune diseases.

(Several years ago Ron Davis pegged the HLA region as a potential study area for ME/CFS. His Stanford Genome Lab has developed new methods of assessing this complex region of our genome, and he and Mike Snyder at Stanford are doing an intensive analysis of that HLA region in ME/CFS.)

Back to Chronic Fatigue Syndrome (ME/CFS)

The highest degree of hypomethylation in a genetic region in ME/CFS occurred in gene promoters associated with natural killer cell functioning, no less – the most consistent finding in ME/CFS. That suggested that some sort of epigenetic reset – perhaps triggered by an infection – occurred in the NK cells of ME/CFS patients.

It was the immune genes, though, where the hypomethylation really came to the fore. Immune genes that regulate the adaptive immune response (T & B cells) and the production of immunoglobulins were hypomethylated. The authors asserted that those findings were in sync with reports of improvement from Rituximab.

Promoters (MMP14, MAP4K4, MAPK12 and CREB5), which may be activating tumor necrosis factor signaling pathways and thus contributing to the pro-inflammatory problems believed present in ME/CFS, were hypomethylated as well.

A gene (miRNA-148a) that impairs the innate immune response was also hypomethylated. Several of the hypomethylated genes were also found in prior ME/CFS studies.

Then there’s the IL21R gene. The hypomethylation of the IL21R gene promoter in ME/CFS could promote inflammation, autoimmunity, thyroid disease, intestinal inflammation, and others. IL-21 also plays a critical role in triggering spontaneous experimental autoimmune encephalomyelitis – an animal model of brain inflammation.

Conclusion

Epigenetics is a relatively new science which is already proving to be a boon to the study of autoimmunity and cancer. Larger studies will be needed in ME/CFS for epigenetics to reach its potential, but the study from Dr. Klimas’s group suggested that, just as in some autoimmune diseases, enhanced hypomethylation may be increasing the expression of genes which promote inflammation and autoimmunity in ME/CFS.

The most encouraging thing about epigenetics is the possibility of reversing the epigenetic changes a pathogen, toxin or drug has caused. Much more study is needed to isolate any epigenetic culprits in ME/CFS, but epigenetic altering drugs are being developed for other diseases. One intriguing drug seeks to reverse the epigenetic changes caused by herpes simplex virus – thus returning the immune system to normal. Another breakthrough suggests that epigenetic changes may be major drivers of multiple sclerosis.

Looking for clues to the cause of chronic fatigue syndrome (ME/CFS), Ian Lipkin has, over the years, poked his fingers into a number of different areas. His 2012 XMRV study showed that the virus was not infecting people with ME/CFS. (It was a contaminant). His pathogen studies (unpublished) found no evidence of a viral infection in ME/CFS.

Subsets

Lipkin may have uncovered more potential subsets than any other researcher and has long emphasized the need to break ME/CFS up into its constituent parts.

Lipkin believes identifying subsets is critical to the progress in this field

Lipkin and Mady Hornig’s 2015 cytokine study which found the immune system going gangbusters early in ME/CFS but then pooping out, exhausted, later identified two possible subsets (early and long duration patients.) Lipkin then teamed with the Simmaron Research Institute to document similar findings in chronic fatigue syndrome (ME/CFS) patients’ spinal fluid. Dr. Peterson, Lipkin and the Simmaron Research Institute then uncovered an atypical ME/CFS subset (the “Peterson subset”.)

In an email Lipkin emphasized the critical need to identify the subsets he believes must be present in this disease.

ME/CFS is not a single disorder and is unlikely to have single cause or a single treatment. As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

Over the past couple of years Lipkin – who has been intensely interested in the role that gut bacteria plays in this illness – has been digging into an ME/CFS plus irritable bowel subset. We’ve learned in the past ten years just how influential the gut is. Gut bacteria and the metabolites they produce don’t stop at the gut. If they leak out of the gut they can directly affect the immune and central nervous system functioning. Some of the metabolites showing up in ME/CFS metabolomic studies originate in the gut.

Last year Lipkin’s group published the most comprehensive gut bacteria study in ME/CFS yet done, which incorporated immune and clinical findings. This year he repeated the gut bacterial analysis and added metabolomics and clinical findings to the mix. The man clearly likes large, complex studies.

The 2017 Gut Study

The large 2017 Nagy-Szakal/Lipkin gut study was notable for it’s size (n=100) and it’s breadth – it included patients from no less than six ME/CFS practitioners including Dr. Peterson. It found, amongst other things, increased levels of bacteria from a family (Clostridiaceae) known for its abundance of toxic and disease causing bacteria.

One of the few gut studies that’s actually been able to identify individual bacterial species, the study found increased abundances of several bacterial species (Faecalibacterium & Coprococcus spp.) that have been associated in other studies with IBS-like symptoms, including colonic pain, bloating, and GI discomfort.

Using a type of data analysis called topological data analysis (TDA) which is able to incorporate metagenomic, metabolic pathway, immune and clinical data, the Lipkin group found that the presence of irritable bowel syndrome (IBS) was having a major effect on disease severity, gut microbiota, and immune profiles.

That finding led the Lipkin group to split the ME/CFS patient cohort into ME/CFS with IBS and ME/CFS without IBS subsets and examine the differences in microbiota (gut bacteria).

The gut bacteria in the ME/CFS plus IBS subset was different from the ME/CFS only group and the healthy controls

The results were astonishing. A dissimilarity measure found that gut bacteria differed as much between the ME/CFS + IBS patients and the ME/CFS – IBS patients as between the ME/CFS group as a whole and the healthy controls. That analysis suggested that the guts of the ME/CFS patients with and without IBS featured significantly different bacteria.

The cytokine data in the study did not add to the analysis but the microbiome analysis revealed a number of interesting possibilities,

Metabolic pathway analyses revealed the ME/CFS + IBS and the ME/CFS – IBS groups differed in some important ways. Both groups featured enriched metabolic pathways that produced Vit. B6, but an important part of the energy production process (the pyrimidine ribonucleoside degradation pathway) was enriched in the ME/CFS only group. That same pathway was hit hard in the ME/CFS plus IBS group.

Plus, the abnormalities found in the urea cycle, which is closely linked to aerobic energy production (Krebs or TCA cycle) occurred mostly in the ME/CFS + IBS group.

The data suggested that people with ME/CFS and IBS group had different bacterial gut makeups and might have more problems with energy production than people with ME/CFS, and it set the stage for Lipkin’s next effort.

After striking that rich vein, the Lipkin group expanded their research effort – incorporating metabolomics for the first time into their studies. (Lipkin and the Simmaron Research Foundation are also currently engaged in the first metabolomics spinal fluid study.) Once again incorporating a wide variety of doctors from different locations (Peterson, Bateman, Klimas, Levine, Montoya) and using a fairly large sample set (n=100) Nagy-Szakal/Lipkin, the Lipkin group fused together blood metabolomic, fecal bacterial metagenomic, and clinical data to paint a new picture of ME/CFS.

The study represented the first attempt to meld two potentially important fields in ME/CFS – metabolomics and gut microbiome findings- together. Lipkin and Hornig have proposed that the gut issues play an important role in ME/CFS, and several studies have found evidence of dysbiosis (pro-inflammatory gut bacteria) in ME/CFS. Unutmaz is chasing down a T-cell gut connection, and past studies have suggested that bacterial leakage from the gut could help explain at least some of the post-exertional malaise present.

Given the group’s past gut findings – that significant differences in gut bacteria, immune profiles and possibly energy production exist between ME/CFS + IBS patients and ME/CFS patients without IBS, it made sense for the Lipkin group to once again split the ME/CFS group into subsets with and without IBS and analyze the heck out of them.

Study Results

Energy Production Problems Highlighted

The study confirmed past general findings of decreased levels of phospholipids and sphingomyelins – two important findings by Naviaux- and increased levels of triglycerides (TG’s). (Triglycerides have been associated with metabolic problems and hypothyroidism.)

That both the ME/CFS + IBS group and the ME/CFS without IBS group had reduced levels of metabolites associated with the choline-carnitine energy pathway suggested that both groups had similar core metabolic problems. (Carnitine participates in the TCA cycle, ATP production and energy metabolism).

More Was Better

The Lipkin group’s decision to integrate metabolomics, microbiome and clinical data worked. Not only did incorporating all this data together illuminate a possibly important subset – the ME/CFS IBS subset – but it also allowed the group to better differentiate ME/CFS patients from controls. It suggested that studies which combine multisystemic data together will do a better job in describing this multisystemic disease.

As with the 2017 study, having or not having IBS was the biggest driver in determining the kind of bacterial profile (and bacterial metabolic pathways) present. This time the study found that the metabolomics of the ME/CFS + IBS group were significantly different from the ME/CFS only group as well. That suggested these two subsets of ME/CFS patients might be quite different indeed.

In contrast to Naviaux, the study did not find a “consistent decrease” in ceramide metabolites – the most commonly disrupted metabolite Naviaux found in his ME/CFS group. When Lipkin controlled for IBS, he found increased levels of ceramides in the ME/CFS plus IBS group but decreased levels of ceramides in the ME/CFS only group. That suggested that key metabolites in ME/CFS might be different in these two ME/CFS subsets.

Nagy/Lipkin suggested that increased levels of bacterial toxins (IBS connection) in ME/CFS may be triggering an enzyme called sphingomyelinase to produce the ceramides which then may damage the gut lining and possibly interfere with energy production.

The metabolomic analysis suggest unique metabolic problems may be present in the ME/CFS plus IBS group

Ceramides are waxy fats that figure in a number of processes that may be important in ME/CFS. Not only can they produce many free radicals (reactive oxygen species) that can damage the gut lining (the IBS connection), they can also interfere with electron transport (the energy connection) as well as contribute to insulin and leptin resistance (metabolism issues).

The authors also proposed that the higher mannitol levels found in the ME/CFS could reflect the breakdown of two important barriers in the body: the gut barrier and the blood-brain barrier.

Several studies suggest a breach in the gut barrier could be contributing to systemic inflammation in ME/CFS, and one suggests that exercise may further widen that breach. Several researchers, including Jarred Younger and Avindra Nath, have also postulated that the suspected neuroinflammation in ME/CFS results from immune cells entering the brain through a weakened blood-brain barrier.

The Gut Shines in Distinguishing ME/CFS Patients From Healthy Controls

Interestingly, for all the focus on metabolomics, a network analysis using differences in gut bacterial abundance was better able to distinguish ME/CFS patients from healthy controls than did metabolomic results.

That suggested that gut bacterial differences may be more prominent than metabolomics differences in ME/CFS patients. That was a surprise, and we’ll see how this all turns out. It stands to reason that the closer we get to the core of the problem, the more striking the differences we’ll see between healthy people and people with ME/CFS. (Will the gut play a bigger role than we thought?)

Possible Treatment Options

The group suggested that their findings, if validated, could present some possible treatment options. They included using SMAse blockers to reduce ceramide levels and giving carnitine supplementation to increase the low levels of metabolites in the choline-carnitine pathway. One open-label study found that carnitine supplementation helped over half of ME/CFS patients.

Given the unrevealing cytokine data from Lipkin’s cytokine data and his recent turn to metabolomics I asked Lipkin how important a role cytokines were likely to play in future ME/CFS research and treatment. Lipkin felt they may yet play an important role in ME/CFS indeed:

“Cytokine disturbances can result in fatigue, cognitive and other disturbances. The observation that other biomarkers such as metagenomic or metabolomic profiles are highly associated with disease does not diminish their (cytokines) importance. There may be people who would benefit from drugs, including antibody therapies, that modulate cytokine responses.”

Scheibenbogen is pursuing antibody therapies in ME/CFS, and Nancy Klimas is reportedly using Enbrel (etanercept) – a cytokine (TNF) blocker – plus mifepristone in her Gulf War Illness trial. Other biologics are available and more are coming on the market. Recent findings in POTS suggest that antibody drugs will probably play an important role in that disease as well.

Since the study also found that taking Vit. B supplements was associated with higher levels of pantothenic acid and lower fatigue scores, taking Vit. B supplements may be a good idea.

The 5-MT Question

Decreased levels of 5-MT, a metabolite associated with tryptophan, serotonin and melatonin metabolism could reflect problems with serotonin/melatonin conversion. This finding, however, was confounded by the high use of antidepressants (50% of the ME/CFS group) which could have produced the decrease.

Correlation studies do suggest, though, that low 5-MT levels could contribute to problems with cognition, sleep and fatigue. Larger studies are needed to determine if the low 5-MT levels are associated with those symptoms in ME/CFS – and if they are – if it might be beneficial to modulate that pathway using drugs in ME/CFS.

Next Up for the Simmaron Research Foundation and Ian Lipkin

The next phase in the Simmaron Research Foundation’s ongoing collaboration with Ian Lipkin is an expanded study which will, for the first time in ME/CFS, analyze the metabolomics of ME/CFS patients cerebral spinal fluid. The study, which will also include immune analyses is the third Simmaron/Lipkin CSF study to date. The first two studies found dramatic evidence of immune activation and the presence of a potential new subset.

Lipkin also reported rapid progress from his new NIH research center and a new collaborative effort with ME/CFS researcher and NIH ME/CFS research center leader Derya Unutmaz. The idea of two top labs in the country collaborating in a complementary fashion is an exciting one – one we will hopefully see much more of in this field.

Lipkin and Unutmaz are merging their respective strengths in a collaboration – something we could use much more of in ME/CFS.

We are completing analysis of saliva, blood, and feces for bacteria, viruses and fungi from ME/CFS and control subjects using powerful new sequencing methods. This will be the largest and most comprehensive study to date on the microbiome in ME/CFS. We will soon begin metabolomic, proteomic, and transcriptomic analyses of ME/CFS and control subjects before and after exercise. We are deeply grateful to the patients who are contributing to this work despite the implications for their health. They are true heroes.

We have begun a new collaboration with Derya Unutmaz and Jackson Laboratories that builds on the complementary expertise of our teams in cellular immunology and molecular microbiology and biochemistry.

Dana March and Tony Komaroff are building an app to help ME/CFS subjects and their caregivers track their status. We have had great support in this effort from people in the community.

Conclusions

In the past three years Lipkin’s identified three potential subsets (early/late duration patients, the “Peterson subset”, ME/CFS + IBS subset) and his explorations into the ME/CFS IBS subset continues to reap dividends.

Dr. Ian Lipkin, Center for Infection and Immunity, Columbia University

His metabolomic study found signs of energy production problems in all ME/CFS patients, but when Lipkin separated out the ME/CFS + IBS patients, he found altered, even at times opposite metabolic findings that could suggest a different source of fatigue was present in the ME/CFS + IBS patients. His earlier study suggested more severe energy production problems may be present in ME/CFS patients with IBS.

The importance of the gut bacteria in ME/CFS perhaps rose to a new level of significance when a network analysis found larger differences in gut bacteria than metabolites. Lipkin’s ability to better differentiate ME/CFS patients from healthy controls using gut bacteria, metabolomic and clinical data suggests that large studies which tie together multiple systems will be the most helpful.

In short, the latest study from the Lipkin group indicates that the gut does matter in ME/CFS and that in those with gut problems it may matter more than we think.

The Simmaron Research Foundation and Lipkin are employing metabolomics in the study of cerebral spinal fluid for the first time, and Lipkin has launched a new collaborative ME/CFS effort with fellow NIH ME/CFS Research Center leader Derya Unutmaz.

Inflammation, the brain and energy metabolism – it’s like the trifecta in chronic fatigue syndrome (ME/CFS) research. It seems like virtually everyone in the ME/CFS field believes that all three are involved but that belief only carries so much weight in a small field. What this field really needs is buy-in from outside researchers who can help move it forward.

That appears to have happened recently when a major research group lead by Robert Dantzer penned a review paper proposing that low-grade inflammation is causing energy production problems in chronic fatigue syndrome (ME/CFS) and probably many other diseases. The authors didn’t shy away from the chronic fatigue syndrome (ME/CFS) connection. In fact, they lead their review paper off with it, placing the fatigue in ME/CFS in the same context as the fatigue in cancer, MS, rheumatoid arthritis and others.

The study was published in the Frontiers in Neuroscience journal series which is touted as the 1st most cited series in the Neurosciences journal field.

The Dantzer group’s involvement in the intersection between inflammation and energy production is welcome but not entirely surprising; it’s a logical outcome of their past work. Dantzer spearheaded the now accepted idea that the immune system produces the symptoms of “sickness behavior” (fatigue, headache, muscle aches, sore throat, etc.) that occur during an infection which serve to reduce our energy usage and to keep us isolated from others (they posit to prevent pathogen spread).

What’s new is his group’s focus on the energy production process itself – a focus, interestingly, made possible largely by the work of ME/CFS researchers. The piece, with lead author Tamara LaCourt, shows how low-grade inflammation can cause the same energy problems we’re seeing in ME/CFS: a metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach.

Immune cells aren’t like other cells; jumping into action causes them to rev their motors up tremendously, placing enormous stress on their energy production systems. As they do this, they switch from a focus on aerobic energy metabolism to what the authors call “aerobic glycolysis” in order to churn out energy more quickly. That process results in less mitochondrial energy production and the increased production of toxic by-products like lactate. Plus, over time this process results in reduced nutrient availability and less energy for the rest of the body.

The authors believe that inflammation and metabolic and energy problems come together to produce a final common endpoint: fatigue.

Several studies from the Solve ME/CFS Initiative are examining whether the energy production of immune cells in ME/CFS is up to the task.

Prolonged inflammation also tends to result in two other energy production problems: increased insulin resistance and reduced glucose tolerance. Reduced glucose tolerance smacks glucose uptake by immune cells at the very time that they’re clamoring for it, causing the body to break down fats and proteins, thus removing resources it would ordinarily use elsewhere. In yet another whack at the energy production, inflammation increases reactive oxygen species production which can hammer mitochondrial energy production.

The authors believe that neurons – which rely on glycolytic processes in astrocytes to get their energy – may be hit hardest by chronic inflammation. This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.

Miller’s work on ME/CFS suggests that problems with the basal ganglia – the dopamine-producing center of the brain – may be causing problems with movement, reward and fatigue in ME/CFS. That’s a particularly interesting finding given that dopaminergic neurons in the brain are particularly vulnerable to inflammation. Shungu’s studies, which have consistently found high lactate and low gluthathione levels in the ventricles of ME/CFS patients brains, suggest that high levels of oxidative stress could be causing inflammation in the brain itself.

Plus, even low-level inflammation can disrupt a key element in ME/CFS and FM – sleep – which, in turn, increases fatigue. Simply altering one’s circadian rhythm (i.e. one’s sleep times) can have significant metabolic effects, leading to increased glucose levels and decreased insulin sensitivity. The effects don’t end with sleep; sleep deprivation results in the need for increased energy expenditures the next day.

Then add in the extra ten percent in extra energy needs that chronic low-level inflammation imposes on the body – and the potential for a dramatic drop in energy production rises. (We’ll find out more about total energy production in ME/CFS during the metabolic chamber tests in the NIH’s intramural study).

The authors believe that impaired energy production represents a “final common pathway” in persistent fatigue.

Leader in the Field

“In sum, most evidence for an association between fatigue and mitochondrial functioning comes from CFS, indicating lower levels of antioxidants and possible reductions in mitochondrial ATP production.” The authors.

We understandably don’t think of researchers in the small ME/CFS research field as being pioneers in the medical research field at large, but some have ploughed brand new ground. Suzanne Vernon’s computational biology work at the CDC was so novel that an entire issue of the Pharmacogenomics journal was devoted to it. Gordon Broderick and Travis Craddock’s expansion of that work at Dr. Klimas’s Institute of NeuroImmune Medicine has taken computational biology further – much further – in ME/CFS than in any other field. Ron Davis and Mark Davis at Stanford are using new HLA gene typing and T-cell technologies to try and nail down what is activating ME/CFS patients’ immune systems.

ME/CFS researchers’ attempts to understand the intersection between mitochondrial problems and fatigue are clearly breaking new ground as well. According to the authors of this review article, 21 of the 25 studies examining the intersection between mitochondrial problems and fatigue have been produced by ME/CFS researchers. Researchers we all know ( e.g. Naviaux, Montoya, Hornig and Lipkin, Fluge and Mella) were cited again and again in the overview.

The authors even cited Workwell’s groundbreaking 2013 study which indicated that a shift to glycolytic energy production occurred during the second day of a two day exercise test in ME/CFS. They also singled out the 2017 Tomas study which found that under conditions of cellular stress, the mitochondria in ME/CFS patients’ cells were unable to rise to the occasion.

Turning to the metabolomics studies, the authors cited three ME/CFS studies which have pointed to “reduced metabolic activity”. They believe the metabolic changes seen in ME/CFS reflect a chronic over-reliance and eventual depletion and abandonment of lipid metabolism, which results in a greater use of carbohydrate stores; hence the greater reliance on glycolysis and impaired aerobic energy production. In short, the authors believe the metabolomic studies in ME/CFS are demonstrating the same metabolic shift that the authors propose occur in states of chronic low-grade inflammation.

Interestingly, the authors proposed that many ME/CFS patients are probably exceeding their daily energy stores. That, of course, makes perfect sense given Staci Stevens’s and Workwell’s findings that, for some patients, simply sitting upright puts them into an aerobic energy deficit.

For all its possible connections, the idea that fatigue in ME/CFS is simply the result of “low-grade inflammation” seems untenable given the disability present – unless that inflammation is found in the brain. The Simmaron Research Foundation is bringing the brain, the immune system and metabolism together in a way that’s never been seen before in ME/CFS.

The Simmaron Research Foundation’s first ME/CFS cerebral spinal fluid study suggested that an immune dysregulation, the likes of which approached that found in multiple sclerosis, may be present in the ME/CFS patients’ central nervous systems. Their second outlined an atypical ME/CFS subset. Their current CSF (cerebrospinal fluid) study – an expanded version of the first study which includes a metabolomic component – will be the first to potentially merge immune and metabolic findings in the most energetically active part of the body – the brain.

The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. Rivas et. Al. 2018

Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out. (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)

The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)

NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.

Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.

If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.

A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.

Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells have trouble fighting off herpes viruses.

NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.

Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.

Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).

This larger, fresher (quick analysis of blood), stricter (CCC patients only) and more comprehensive study found differences where others had not – and plenty of them. This group validated – with a high degree of certainty (p = 0.0075) – previous findings of an increased subpopulation of NK cells (NK CD56++(high)) which, get this, excrete more cytokines (particularly IFN-y), possibly causing more symptoms, but which have low cytotoxic activity. Because these cells have unusually long life spans and pump out cytokines that cause more T-cell proliferation, higher numbers of them could contribute to autoimmunity and inflammation.

These cells were particularly high in the group of patients whose illness began without evidence of an infection. The Spanish group suggested that activation of the stress response via the HPA axis and raised levels of catecholamines such as norepinephrine (adrenaline) could have triggered the expansion of this potentially autoimmune affecting natural killer cell subset.

No differences were found, however, in the levels of several receptors (NKp46, NKp30, NKp44) that have been found elevated in some autoimmune/inflammatory conditions (Sjogren’s Syndrome, Crohn’s disease) or reduced in chronic infections (HIV, tuberculosis, influenza, etc.).

Increased levels of the CD 69 marker suggested autoimmunity may be present in ME/CFS

Reduced levels of a receptor (NKG2C) were very common (p<0.0001) in ME/CFS. When this receptor, which is only found in NK cells, is activated by the presence of virally infected cells, it triggers an expansion of NK cells. Not surprisingly, NK cells become dotted with this receptor in people with chronic herpesvirus and other infections (HCMV, EBV) but ME/CFS patients’ NK cells had consistently lower levels of this receptor than did the healthy controls. The authors didn’t speculate why this occurred, but it could involve lower levels of infection in ME/CFS – something Ron Davis is finding in his severely ill cohort – or a problem responding to infections that are present.

That second possibility was buttressed by an inverse correlation found between a marker of infection (CD 57+) and the lower expression of a marker (NKp46) which is often reduced in herpesvirus infections. The authors suggested that the scenario found in ME/CFS (increased cd57+, lower NKp46, high NKG2C) could reflect HCMV (cytomegalovirus) reactivation.

Increased levels of the CD69 marker (p= 0.011) provided another suggestion that ME/CFS may be an autoimmune/inflammatory disease. This important marker, which is found on many immune cells, stimulates NK cell cytotoxic activity. More importantly, CD69 has been described as a master regulator for autoimmunity in rheumatoid arthritis (RA) through its upregulation of TGF-B – one of the very few cytokines that has usually been found increased in ME/CFS.

A “descent” in T regulatory cells similar to that found in autoimmune conditions such as lupus and RA was also found. Finally, an inverted Th17/T regulatory cell ratio, which is also found in autoimmune conditions like lupus, wrapped up the autoimmune connections found in this study.

Using a mathematical classification model, the group was able to correctly diagnose 70% of ME/CFS patients and healthy controls simply by using the findings from this in depth study of natural killer cell populations.

Conclusions

This large Spanish study of NK cell subpopulations found numerous irregularities in NK cell types in ME/CFS, several of which pointed to issues with autoimmunity and/or inflammation. As in other studies, this study indicates that larger is indeed better when it comes to studying ME/CFS.

The study validated prior findings of an unusually large set of NK cells which produce more cytokines – conceivably causing more symptoms and immune activation – but which are less effective at killing infected cells. That finding seemed to jive with a picture of highly symptomatic ME/CFS patients who may have trouble fighting off infections.

While no differences were found in the levels of receptors which can be elevated in autoimmune conditions, several other findings suggested that NK cells may be fighting off herpesvirus infections or may be involved in autoimmune/inflammatory processes in ME/CFS.

Finally, using just NK cell subpopulation data, the authors were able to correctly identify 70% of patients and healthy controls, indicating that significant NK cell differences exist. All told, the study identified several natural killer irregularities that could participate in autoimmunity and dysregulate other parts of the immune system.

Dr. Nancy Klimas: From Biomarkers to Modeling and Clinical Trials; GWS and ME/CFS

Years of work appear to be coming to fruition for Dr. Klimas. Her ability to hook into GWS funding has made a huge difference in her ability to test out her modeling protocols. It’s remarkable to see the Dept of Defense lay down $40 million per year for the vets affected during the Gulf War 27 years ago, while ME/CFS gets so little. The vets undoubtedly deserve it and they deserve more – many lives were shredded as a result of the war and they’ve fought for years to get recognition. However, the disconnect between the way the feds have treated GWI and ME/CFS – a disease which affects far more people – is startling. The Dept of Defense hasn’t done great by its vets, but it’s been much more responsive to them than the feds have been to ME/CFS and fibromyalgia.

Years of work appear to be coming to fruition for Dr. Klimas

Dr. Klimas noted that the more we look, the more immune abnormalities are being found. Cytokines may not tell us what is causing ME/CFS, but they sure could help us find drugs to combat it. Klimas is comparing the immune signatures she’s seeing in ME/CFS with those of other diseases and then checking out what’s working in those diseases. The good news is that immune-affecting drugs are big business now, with more and more coming on the market. If ME/CFS is, at its heart, an immune disorder, or if the immune system plays a large role – as many think it does – drugs developed for other diseases may be able to help.

Dr. Klimas and her researchers have been asserting for years that ME/CFS patients are stuck in a kind of suboptimal, self-reinforcing homeostatic space; i.e. their systems have been rewired to produce a new normal.

That idea doesn’t seem to be all that far from Naviaux’s belief that people with ME/CFS are stuck in a Dauer state or Dr. Cheney’s report that while he could push patients towards health, something would pull them back. Both Klimas and Naviaux believe a series of structured moves will be needed to move the system back to normal. Neither believes it’s easy; Klimas says real “force” will be needed to move the system back into health.

Klimas should know – she’s been intensively charting how ME/CFS patients’ systems go off the rails during exercise for several years now. She’s measured every cytokine, neuropeptide, etc. she can at 8 timepoints before, during and after exercise in 50 women with ME/CFS, 25 women with FM, 50 men with ME/CFS and 50 men with GWI.

She’s gathered a vast amount of data and that data is telling her that ME/CFS patients’ immune systems basically go nuts during the first 15 minutes of exercise. Four hours later, oxidative stress kicks in and the autonomic nervous and endocrine systems and metabolism get hit — but it’s the immune system that kicks everything off.

The big surprise is how different chronic fatigue syndrome (ME/CFS) is from Gulf War Illness. The metabolism gets hit hard in ME/CFS – everything gets shut down – but in GWI, all the pathways are ramped up. They’re two completely different illnesses which from the outside look exactly the same.

Dr. Klimas and her team have been running sophisticated modeling techniques on supercomputers to figure out how to get our systems back to normal. Initially, they ran into trouble with women who, no surprise, have much more complex systems than men. Back to the drawing board they went. In the end, Dr. Klimas’s team was able to create a virtual clinical trial in GWS. First, they brought down brain inflammation using etanercept, and then readjusted the HPA axis with a glucocorticoid receptor blocker, mifeprestone.

It worked on the computer – their virtual GWS patient returned to health system – but the big test came with their Gulf War Syndrome mouse model. When the drug combo was able to return the GWS mouse to health they really knew they were onto something. An open label phase I trial in GWS is under way as we speak.

Her team has used supercomputers to create virtual clinical trials

Dr. Klimas noted that the $30 million the DOD is providing for GWI has made a big difference where the rubber meets the road in medicine – in ten clinical trials that are underway. That’s in a disease that effects fewer people than ME/CFS but which receives federal funding for clinical trials. That’s not true for chronic fatigue syndrome (ME/CFS) – federal funding for clinical trials is pretty much blocked.

Researchers can apply for clinical trial funding at NINDS and other institutes, but ME/CFS doesn’t have a chance against diseases like Parkinson’s and Alzheimer’s. The big issue is that the program announcement for ME/CFS – which lists subjects researchers can apply to study – doesn’t allow them to submit clinical trials proposals.

Dr. Koroshetz’s promise last year to get that language embedded into the ME/CFS PA hasn’t paid off yet. Getting that wording embedded into the PA for ME/CFS could open up funding for clinical trials. That would be a big step forward.

Dr. Klimas doesn’t have a mouse model for ME/CFS but she’s been doing the same computer modeling she used in GWS on ME/CFS. It’s clear that nobody at this point understands more about what happens during exercise in ME/CFS than Dr. Klimas. Nobody has been able to translate mountains of exercise data into virtual clinical trials. Nobody has proposed a staggered two-drug approach to ME/CFS, and nobody probably has a better shot at stopping PEM than her. This is new stuff not just for us but for the medical field in general. Let’s hope it works out.

The GWS trial is underway and she hopes to get her chance at halting the PEM in its tracks in ME/CFS in a small trial later this year. Getting funding, of course, will be crucial.

ME/CFS rather suddenly has several drug/drug trial possibilities: they include Cortene, Dr. Klimas’s drug combo, immunoadsorption (see below), Fluge and Mella’s Norwegian cyclophosphamide trial, Ampligen and Dr. Kaiser’s Synergy drug-nutrient combination – and, of course, Rituximab is still surely in the picture for a subset of patients.

Carmen Scheibenbogen

Scheibenbogen is a mover and shaker. She’s published six papers on ME/CFS in the past three years, is a leader in the Euromene Group, has been talking to pharmaceutical companies about drugs, and is organizing a fatigue conference in Germany to get some good networking going.

Dr. Rowe called Dr. Scheibenbogen’s antibody findings one of the most exciting ME/CFS research findings in years.

Peter Rowe called her recent autoantibody papers one of the most exciting recent developments in the field. Scheibenbogen, interestingly, got the idea to do those studies from similar recent findings in POTS (postural orthostatic tachycardia syndrome).

Scheibenbogen rattled off some of the commonalities between autoimmune diseases and ME/CFS. Both predominantly affect women, both are often triggered by an infection and she’s found a high family history of autoimmunity in ME/CFS. Plus, Epstein-Barr virus – a common trigger in chronic fatigue syndrome (ME/CFS) – invades B-cells which are the main drivers of autoimmunity. The difficulty ME/CFS patients and others have fighting off the virus when exposed to it later in life apparently gives the immune system plenty of opportunity to make a mistake and begin attacking our own tissues.

Rituximab is used to treat autoimmune diseases. The Rituximab ME/CFS trial’s main endpoint failed but Scheibenbogen asserted that we shouldn’t count Rituximab out at all. She believes, and she would know, because she’s studied Rituximab patients, that Rituximab will be shown to be effective in a subset of patients. An effective treatment in a subset of ME/CFS patients would be a big deal – particularly for those patients.

Scheibenbogen found increased levels of antibodies in about 40% of ME/CFS patients, and Bergquist’s study that is currently underway thankfully had similar results. At least right now it appears that the 40% figure is solid, but the search for antibodies in ME/CFS is not over. When I asked Scheibenbogen if other antibodies might be involved, she said, yes, other antibodies probably will apply. If that’s so, that 40% number could go up. Scheibenbogen noted that the B2 and muscarinic antibodies that have been showing up in ME/CFS are part of a larger network.

Interestingly, these are not autoantibodies; they’re natural antibodies which affect breathing, the circulation and the gut. Their high levels in ME/CFS appear to be throwing those systems off.

Immunoadsorption

Immunoadsorption is another possible immune treatment for chronic fatigue syndrome (ME/CFS). Immunoadsorption, which is similar to, but more effective than plasmaphoresis, removes IgG autoantibodies from the blood. It’s an expensive treatment – about $20,000.

Like Rituximab it will probably be effective in a subset of patients. Scheibenbogen’s small immunoadsorption trial of ME/CFS patients with specific autoantibodies found that the treatment did what it was supposed to do – it significantly reduced antibody levels for at least six months.

Symptoms improved in most patients and some patients completely recovered. Three are still in remission a year after the treatment ended. One person completely recovered for 6-7 weeks but then relapsed. After she relapsed, she could hardly walk again. The trial suggested that Scheibenbogen is on the right track with her autoimmune studies. The fact that POTS is so prevalent in ME/CFS and has similar autoantibody issues suggests that the outcome is not such a surprise.

The trial was small and carefully curated to those with high antibody levels but most patients improved and some recovered

A follow-up study is beginning. If that works out, Scheibenbogen hopes for a big trial that will settle the issue definitively. In a good sign, she reported that the company that produces the immunoadsorption treatment (not available in the U.S.) is quite interested in ME/CFS.

(Even if the treatment is not available in the U.S., a successful trial could do a couple of things: it could prompt the company to make the treatment available in the U.S., and it would surely enhance autoimmunity research. We’ll see what happens, but if we can come up with several treatments – each of which is effective in a subset of patients – we’ll start to whittle the disease down.)

As she left for the airport, Scheibenbogen said she hopes that in the next five years ways to diagnose and treat ME/CFS will be found. Let it be so…

Guidelines to Biomarker Produced

Euromene, the new ME/CFS European research group Scheibenbogen is working with, recently laid out a step-by-step pathway to develop a biomarker. She noted that we have lots of interesting findings, but none that are unique to ME/CFS. Plus, the findings we do have overlap too much with healthy controls.

In short, we haven’t found that key signature – that key physiological mark – which says a person has ME/CFS. (That may not be a surprise: until we find the core of ME/CFS, we may not be able to find a unique biomarker). Scheibenbogen did wonder, however, given Maureen Hanson’s recent inability to find subsets in her metabolomic data, if the biomarker for ME/CFS will be metabolic in nature.

Unutmaz’s Big Surprise

Ron Davis has noted things often don’t work out the way researchers expect them to. Apparently, Derya Unutmaz feels the same way. Unutmaz got a T-cell result that pointed straight at the gut and then was pleasantly shocked when a look at the gut confirmed his findings. He was expecting a few more twists and turns from the body! It’s not usually so easy.

He noted that over the past decade a tremendous amount of work has been done on the effects the gut microbiome (gut bacteria) have on the immune system. It’s now clear that a shift toward more inflammatory bacteria in the gut can result in inflammation in other parts of the body. In fact, Unutmaz reported that just about every disease is associated with a change in gut bacteria. The bacteria play such a vital role that oncologists can even determine how effectively patients will respond to immunotherapies by assessing the kind of bacteria they carry in their guts.

That makes sense for ME/CFS, since every gut bacteria study has thus far found substantial alterations in the bacteria in ME/CFS patients’ guts.

Unutmaz is a T-cell guy. He knows that bacterial metabolic by-products trigger unusual T-cells called MAIT T-cells (Mucosal associated invariant T cells) to get into action. Once these cells, which are found in our gut lining, liver, lungs, etc., come across those metabolites, they secrete pro-inflammatory cytokines. Those cytokines turn monocyte cells into hairy monsters called macrophages which then gobble up the bacterial-infected cells.

MAIT cells, then, play a key role in turning on our immune response to the bad bacteria that can live in our guts. They apparently lurk in the gut lining as a kind of last line of defense against those bacteria getting into our blood stream and invading the rest of the body.

Unutmaz’s findings suggested that T-cells in the ME/CFS patients’ guts had been repeatedly exposed to bad bacteria

Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present. In true ME/CFS fashion, Unutmaz also found that ME/CFS patients’ MAIT cells were activated — but “punked out” at the same time. (A wired and tired immune cell?). Seemingly exhausted by the continual stimulation, they (like their natural killer cell cousins) had problems killing infected cells. That hearkened back to the Lipkin/Hornig immune finding of activated immune systems in early-duration ME/CFS patients and depleted immune systems in longer- duration patients.

Unutmaz is now trying to identify which bacteria are tweaking ME/CFS patients’ MAIT T-cells so much as to possibly burn them out. If he’s successful, he may have found a target that could quiet down a possibly overworked and burnt-out immune system and allow it to rejuvenate.

Viral Mystery

“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley

I sensed some awe in Ron Davis’s voice as he pushed for more understanding of Epstein-Barr Virus’s effects in ME/CFS during a talk at the Brain Science conference. Davis is not to my knowledge finding much evidence of EBV reactivation in the severe ME/CFS patient study – a surprise – but he is very interested in what happened during that initial EBV infection, which appears to have triggered chronic fatigue syndrome (ME/CFS) in so many people.

A large, complex and very common virus, EBV is responsible for infectious mononucleosis and appears to contribute to numerous autoimmune disorders.

He’s not alone in his “admiration” for the virus. Simmaron’s Advisor, Dr. Daniel Peterson, whose clinical practice and research stemmed from an outbreak in the Lake Tahoe region of Chronic Fatigue Syndrome, has tracked EBV in patients for decades, noting very high titers to EBV and other herpes viruses in subsets of patients.

It’s not surprising that these two important figures have had their eyes on EBV. EBV, after all, is kind of in a league of its own. An invader of B and epithelial cells, the 50th anniversary of its discovery was recently celebrated with numerous reviews. Epstein-Barr was discovered in 1966 by Anthony Epstein and Yvonne Barr. It was the first human virus shown to cause cancer. The sequencing of its large genome in 1995 helped launch the genomic era.

One of the more massive and complicated viruses, it’s one of the very few viruses that’s able to avoid elimination: once EBV infects your B-cells, it’s in your body to stay. It’s able to effectively hide from the immune system and reactivate just enough so that when the infected B-cells die it can move on to other cells.

We’re well equipped to ward off EBV when we’re young – it usually produces only minor symptoms – but as our immune systems alter as we age, that changes. Encountering EBV as an adolescent or adult (infectious mononucleosis, glandular fever) – as increasingly happens in our germ phobic age – often means months of convalescence as our immune systems struggle to ward off this powerful virus.

The problems don’t stop there. We know that infectious mononucleosis (IM) is a common trigger of ME/CFS but coming down with IM/glandular fever in adolescence has also been shown to increase one’s risk of coming down with multiple sclerosis 2-4 fold and lupus by fifty percent. Because of EBV’s ability to remain latent in the body, EBV reactivations are a huge problem for transplant patients with compromised immune systems.

The big question concerning EBV is how a virus which has essentially been latent for decades could contribute to serious diseases like MS and lupus. We now may have the answer. Last week, what will probably turn out to be a seminal paper in pathogen research directly showed for the first time how EBV appears to be able to trigger autoimmune diseases later in life and could conceivably play a role in ME/CFS.

The rather hum drum title of the paper “Transcription factors operate across disease loci with EBNA2 implicated in autoimmunity” in the Nature Genetics Journal hardly hinted at the possibilities the paper presents.

EBV consists of several proteins of which EBNA-2 is one. EBNA-2 is EBV’s main viral transactivator; i.e. it’s a transcription factor that turns on genes in an infected cell that help EBV to survive. Essentially EBNA-2 allows EBV to hijack a cell’s genetics and put them to its own use.

The study – produced by researchers at Cinncinnati’s Children Hospital – demonstrated that once EBV infects B-cells, it turns on genes that have been identified as risk factors for a boatload of autoimmune diseases.

It turns out that even though the virus is, so to speak, latent; i.e. it’s not replicating – its transcription factor is still active – altering the expression of our genes. The genes that it affects just happen to be the same genes that increase the risk of developing lupus, multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes. Apparently decades of genetic assault from EBV’s transcription factor can set the stage or at least contribute to many autoimmune diseases.

Chronic diseases are usually caused by a variety of genetic and environmental factors. Because not everyone with these transcription factors comes down with a chronic illness, other factors must play a role. The authors believe, though, that the gene expression changes induced by the virus in the B cells could account for a large number of people with lupus and MS who fall ill.

“In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases,” Harley

Chronic Fatigue Syndrome and EBV/Infectious Mononucleosis – A Short History

Researchers have been trying to figure out – mostly unsuccessfully- what the heck happens to plunge people with infectious mononucleosis into ME/CFS for quite some time.

Infectious mononucleosis/glandular fever is believed to be a common trigger of ME/CFS

Straus’s small 1989 study reporting high rates of psychiatric diagnoses in ME/CFS patients prior to their becoming ill set a theme in motion which was disproved by two Peter White ME/CFS IM publications. White found IM/glandular fever to be a particularly strong trigger of ME/CFS which he concluded was probably responsible for about 3,000 new cases of ME/CFS a year in the U.K.

A 1992 Swedish study began a trend of examining people with ME/CFS during infectious mononucleosis and afterwards in order to try and determine what happened. That study concluded that whatever happened was not due to EBV reactivation.

In 2010 Taylor found reduced peak oxygen consumption during exercise in adolescents with ME/CFS after IM compared to IM patients who had recovered. Broderick’s finding of altered cytokine networks associated with Th17 in ME/CFS patients following IM suggested immune dysregulation had occurred.

Glaser’s 2005 study suggested that an EBV encoded enzyme produced by a non-replicating form of EBV could be producing symptoms in ME/CFS. Lerner’s 2012 study suggested that antibodies to two EBV produced proteins were commonly present in ME/CFS – suggesting that a prolonged immune reaction to EBV might be occurring in ME/CFS as well.

In 2014 Loebel/Scheibenbogen suggested that ME/CFS patients may be having difficulty controlling the early stages of EBV reactivation. Loebel’s 2017 follow up study suggested that ME/CFS patients’ immune system might be over-reacting to an EBV produced protein and that autoimmunity might be involved.

Leonard Jason’s large IM college student study will hopefully provide clues why some people never recover from it. He’s completing data analysis of a study examining college students who came down with infectious mononucleosis and then ME/CFS. So far Jason has found that at least 4-5% of college students come down with IM while at school.

Treatment Implications

Interestingly, several drugs that are available can block some of the transcription factors EBV has inserted into B-cells. (I was unable to determine what they are.) The authors also hope the study will help spur more efforts to produce an EBV vaccine.

Next For ME/CFS and EBV

Now that we have evidence that EBV/IM contributes to many autoimmune diseases, it’s hard to think that ME/CFS is not somehow involved. Chronic fatigue syndrome is different in that infectious mononucleosis (and other infections) immediately triggers ME/CFS in many people. What we don’t know is if bouts of IM also trigger ME/CFS 5, 10, 15 or more years later as occurs in these other disorders.

Opportunities for Collaboration Open Up

The big question awaiting ME/CFS now is if the abnormal transcription factors associated with the autoimmune diseases in the recent paper are present. The good news is that a study determining that appears to be within reach of an ME/CFS researcher with the technical ability and funds. In an unusual move, the Cincinnati researchers are making the computer code they used available to other researchers.

“We are going to great lengths to not only make the computer code available, but all of the data and all of the results. We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow-up on them.” Weinrauch

“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders” Harley

The Cinncinnati team is providing its computer code free to other researchers

They believe EBV will be implicated in many more diseases, and there is already some evidence that it is. Using the same analytical techniques, they’ve already identified 94 other diseases including many non-autoimmune diseases in which EBV may play a role.

This is one of the few studies in which the researchers are so jazzed by their results that they’ve dropped all pretenses to modesty. The study results need to be validated, but because EBV is so common and is potentially linked to so many autoimmune (and other diseases), it has the potential to rewrite our understanding of how autoimmune diseases arise. The authors fully recognize the potential importance of their finding. The lead author of the study, John Harley, said:

“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley

One of the senior authors of the study stated:

“This same cast of characters is a villain in multiple immune-related diseases. They’re playing that role through different ways, and doing it at different places in your genome, but it’s the same sinister characters. So if we could develop therapies to stop them from doing this, then it would help multiple diseases.” Matthew Weirauch

Remarkable Progress

It’s rare that a clear cause of disease like postural orthostatic tachycardia (POTS) or chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) shows up, but that appears to be what’s happening in POTS.

Researchers are increasingly focusing on autoimmune aspects of POTS

The progress is all the more notable in POTS given the newness of the disease. The name was only coined in 1993 and the disease still lacks a dedicated funding stream at the NIH (but see below). Nor does the NIH track POTS funding the way it does other diseases. It was only recently that the World Health Organization created an ICD code specifically for POTS. While the disease is mostly an afterthought at the NIH, it affects a large number of people (1-3 million in U.S.)

Despite its humble beginnings remarkable progress in understanding the disease is being made. That’s good news for people with ME/CFS given the high incidence of POTS (11-40%) in the disease. Plus it shows that even a small research community can make significant strides in a disease if they target the right area.

Autoimmune Disorder

With its female dominance and often an infectious trigger, POTS, like ME/CFS, has always been a candidate for classification as an autoimmune disease. In fact, autoimmunity has been showing up in orthostatic intolerance in general lately. Plus it’s shown up in an array of cardiovascular diseases including hypertension, cardiomyopathy, myocarditis and cardiac arrhythmias, each of which can cause problems standing.

Orthostatic Hypotension

It turns out there are many ways to mess with our circulatory systems. A University of Oklahoma group has been driving the findings in mostly small studies. In 2012 that group reported that people with orthostatic hypotension, who experience severe drops in blood pressure while standing, commonly had autoantibodies to the receptors on the outside of cells that regulate autonomic nervous system activity. Remarkably, autoantibodies were found in no less than 75% of the study participants.

The adrenergic (B1AR, B2AR) and muscarinic (M2R, M3R) receptors identified affected blood flow across the body. Different symptoms appear to result depending on which receptor is involved.

People with severe blood pressure drops within a few minutes of standing, for instance, tended to harbor B2AR and M3R autoantibodies which affect the vasodilation of our blood vessels. Because our blood vessels constrict or narrow when we stand in order to halt the gravitational flow of blood to our limbs, vasodilation during standing is exactly the wrong strategy.

Other people with dramatic heart rate increases while standing tended to harbor M2R and/or β1AR autoantibodies.

POTS

In 2014 the Oklahoma group’s study in the Journal of American Heart Association found evidence of three autoantibodies in POTS. This time the Oklahoma group predicted they would find autoantibodies to a receptor (α1 adrenergic receptor – α1AR) that causes our blood vessels to contract.

They found that, but in a twist, they also found additional autoantibodies: to the β1AR receptor in all the POTS patients, and vasodilatory autoantibodies to the β2AR receptor in half of them. They believe that these autoantibodies enhance norepinephrine’s effect on the heart; i.e. they increase the heart rate problems in POTS.

Autoimmune processes that affect the blood vessels may define disorders that produce problems with standing.

They posit, interestingly, that problems with blood pressure not heart rate increases are the primary problem in POTS. They believe that when POTS patients stand, their α1AR autoantibodies smack the αIAR receptors, causing problems with blood vessel contraction. That allows blood to drain from POTS patients’ brains into their lower bodies causing fatigue, dizziness, etc. In order to compensate, they jack up their sympathetic nervous system activity with norepinephrine in order to maintain blood pressure.

Unfortunately, since POTS patients also harbor autoantibodies which cause them to increase their heart rates, the result is sometimes astonishingly high heart rates while standing. Since a heart beating too fast has the same effect as a heart beating too low (reduced blood flow), the ploy doesn’t work and POTS patients experience dizziness, fatigue, etc. upon standing.

In effect the POTS patients struck out on two levels; not only did they have autoantibodies that might be imperiling their ability to maintain their blood pressure while standing, they also had autoantibodies that dramatically increased their heart rates.

New Study – New Autoantibody

In a follow up 2018 study published in the Journal of the American Heart Association, the group looked at an entirely different type of autoantibody – the angiotensin II type 1 receptor (AT1R) that regulates blood pressure via the renin-aldosterone system. The renin-aldosterone system also regulates blood volume, which is often low in ME/CFS.

The study was again small (17 POTS patients) plus 16 controls, but once again the results were highly significant with 12/17 POTS patients but none of the controls exhibiting autoantibodies to AT1R. Plus all the POTS patients also had autoantibodies to either or both of the AT1R and the α1‐adrenergic receptor.

Because the renin-angiotensin-aldosterone system works more slowly than the aforementioned responses, it appears that many POTS patients may suffer from both a rapid and a more prolonged dysregulation of their circulatory systems. When placed in a rabbit model, the ATIR autoantibody effectively duplicated the effects of the α1AR autoantibody – it stopped the blood vessels from constricting properly, again resulting in blood pooling in the lower extremities – and in humans feelings of fatigue, dizziness, etc.

In a nice fit, several POTS studies have documented problems with the renin-angiotension-aldosterone system, which could be caused by autoantibodies like ATIR. One study, which found elevated Ang II levels and low aldosterone levels, suggested that receptor problems were interfering with transformation of Ang II to aldosterone. The authors of this study suggested that the autoantibody found could indeed be the missing link.

Another Autoantibody (!)

We’re still not done with autoantibodies in POTS. A recent presentation which found a fourth autoantibody (to the M1 receptor) suggested POTS patients may be swimming in autoantibodies which negatively affect their circulatory systems.

Spectrum Disorder?

These investigators believe POTS is part of a spectrum of diseases (OH, POTS, cardiovascular diseases, (ME/CFS?)), all of which harbor autoantibodies that interfere with blood vessel contraction/dilation and the heart rate.

Dysautonomia International – Moving Forward on POTS

Since being co-founded in 2012 by Lauren Stiles, Dysautonomia International has grown rapidly and is now providing substantial funding for POTS research. A very dynamic organization, I was glad to have the opportunity to ask its President about its POTS work, where we are on autoimmunity and POTS, and DI’s recent advocacy work.

What kind of POTS funding has Dysautonomia International provided?

Dysautonomia International has grown rapidly in just five years.

Dysautonomia International has funded over $300,000 in POTS Research Fund grants to support the work of Dr. David Kem and colleagues at University of Oklahoma, exploring the role of autoimmunity in POTS, seeking to identify diagnostic biomarkers, and eventually the development of targeted immune therapies. Dr. Kem’s recent publication documenting the presence of angiotensin receptor antibodies in POTS was one of several important publications that resulted from these grants, and there are additional autoimmune POTS related studies still in progress at the University of Oklahoma. We have also funded autoimmune POTS related studies at Mayo Clinic and University of Texas Southwestern, which are in progress.

How far are we from establishing that at least a major subset of POTS patients have an autoimmune disease?

Most POTS experts acknowledge that a subset of POTS patients have an autoimmune problem. Defining what percentage of patients that is depends on how we define what we mean by “an autoimmune problem.”

For example, the largest cohort study on POTS to date with over 4,000 patients enrolled (lead by Dysautonomia International, Vanderbilt University and University of Calgary), found that 16% of POTS patients report being diagnosed with a known autoimmune disease, most often Hashimoto’s, Sjogren’s, lupus and celiac.

Then there is a larger group of POTS patients who have positive blood tests on common antibody tests, such as TPO, ANA or SS-A, but they don’t meet the criteria for a known autoimmune disease.

POTS patients have signs of an autoimmune disease but larger studies are needed to validate them.

Then we have several small cohort studies, usually 40 patients or less, showing that nearly all POTS patients have antibodies to various cell surface receptors that play a role in regulating the autonomic nervous system (adrenergic, muscarinic and angiotensin antibodies).

This last category of antibodies are also present in other medical conditions, several of which are associated with autonomic dysfunction, such as orthostatic hypotension, Sjogren’s syndrome, Chagas disease, dilated cardiomyopathy, and ME/CFS.

We need a lot of additional research before we can go from “we found these interesting antibodies that might play a role in POTS” to “we’re sure POTS is an autoimmune disease,” but that research is happening at several universities. The antibody tests are being refined. The small cohort studies are being repeated on larger cohorts. Researchers are starting to look at immune modulating treatments too.

I’m proud to say that Dysautonomia International is very much part of this effort, not only funding many of the studies, but also facilitating the larger cohort studies at our annual conferences, and connecting researchers who should be talking to each other together.

The NIH didn’t have a dedicated funding platform for POTS research but now things are looking up. What happened?

After Dysautonomia International’s July 2017 Lobby Day and our first Congressional Briefing on POTS in October 2017, Congress adopted our requested language directing the NIH to “stimulate the field’ of POTS research and “develop strategies that will increase our understanding of POTS and lead to effective treatments.” We’re continuing to meet with NIH to see what this will lead to in 2018, which we hope will be NIH’s first POTS specific call for proposals. Find additional details on our blog.

Conclusion

The POTS autoimmune finding are helpful for ME/CFS in several ways. For one they show that researchers even in greatly underfunded diseases can make substantial progress if they target the right area. Secondly they’re beginning to demonstrate a strong autoimmune basis for a disease which produces similar symptoms to ME/CFS and which has a substantial overlap with it. Finally some of the same autoantibodies (and other ones) have been found in ME/CFS and interest in ME/CFS as an autoimmune disorder is picking up. A recent review paper presented evidence that at least a subset of ME/CFS patients have an autoimmune disease. That will be covered in a future blog.

German Researcher Steps Up

Carmen Scheibenbogen MD is another sign that the ME/CFS field is slowly but surely hopefully catching on. Scheibenbogen is relatively new to this field, but she’s not new to medical research. A trained oncologist and hematologist as well as a physician and Professor of Immunology in Berlin, her research resume includes over 150 publications dating back 25 years.

Dr Scheibenbogen has identified what she believes is an autoimmune subset in ME/CFS. (Image from Invest in ME)

In short, she’s a respected and established researcher, and one from Germany to boot. (I can’t remember the last German researcher to take on ME/CFS.) Her path to ME/CFS has not been an easy one. Germany hardly acknowledges ME/CFS as a disease, and doesn’t fund ME/CFS research – if I’m reading her right, there is apparently literally no avenue to apply for ME/CFS research funding there.

Yet she’s very quickly become one of our most prolific researchers. Over the past four years her team has published no less than seven papers, has won two Ramsay Awards, and played a central role in the development of the new European Research collaboration, EUROMENE. Her biosketch lists CFS/ME, Immunodeficiency, and Cancer Immunology as her main research interests.

Scheibenbogen’s first ME/CFS publication In 2014 found ME/CFS patients mounting a feeble response to Epstein-Barr virus (EBV) . The reduced response to EBV reactivation could help explain the ups and downs seen, particularly during stressful situations.

In 2016, figuring that when Rituximab worked in ME/CFS it probably did so by whacking antibody producing B-cells, her group examined antibodies against a variety of receptors that affect blood flow, the autonomic nervous system, etc. They found that about 30% of ME/CFS patients in a large study (n=293) had increased levels of antibodies to adrenergic (B2) and/or muscarinic M3/M4 acetylcholine receptors (M3/M4).

That suggested that the immune systems of a significant subset of ME/CFS patients might be attacking the receptors on cells which regulate blood flow, lung functioning, muscle contractions and attention. Furthermore, the finding (a “remarkable” one they said) that the antibody levels of two receptors correlated with a host of immune factors (immunoglobulin levels, T cell activation, elevated ANA, TPO antibodies) suggested that this subset of ME/CFS patients are suffering from an autoimmune disease. Scheibenbogen has suggested that the kind of ME/CFS you have may be dependent on the kind of autoantibodies present in your system.

They used a blood purification technique called immunoadsorption to eliminate the B2 antibodies from people with ME/CFS who’d had a post-infectious onset and high B2 antibody levels. Immunoadsorption (IA) was given five times over seven days to completely wash out the antibodies. Over the next six months the participants’ symptoms, muscle strength, endothelial functioning and immune factors were watched.

Findings

Significant improvement eventually followed by a relapse was the order of the day. One patient who could barely walk prior to the treatment was able to walk several hundred yards at the end of the IA process. She completely recovered for seven weeks and then relapsed. Another patient improved enough to go back to work but then relapsed. Five patients who improved started to relapse by the end of the six months. Three patients – a good third of the study – felt significant improvements in fatigue lasting at least 12 months.

The levels of all four antibodies (B1, B2, M3 and M4) declined after the treatment in all 9 participants. These are good results which are hampered by the small sample size and lack of a placebo control. Through our experiences with Rituximab, Synergy and Mirogabalin we’ve learned how little to trust early results. Still, research has to start somewhere and the results thus far present hope for a significant subset of ME/CFS patients.

Present and Future Work

Ramsay Award Standout

The Solve ME/CFS Initiative (SMCI) provides funding to five or so researchers every year in its Ramsay Awards. The Awards are quite competitive with SMCI receiving far more applications than it can fund, but over the past two years the Scheibenbogen group has won two – the only group to do so.

2016 Award

Citing “ample evidence of an autoimmune pathomechanism” the Scheibenbogen team will be digging into the genetics of their “autoimmune subset”. They’ll be determining if genetic abnormalities in the enzymes or transcription factor that turn on the autoimmune processes are present. They’re also analyzing the immune cells (dendritic cells, regulatory B-cells) known to produce autoimmune responses.

This is one of the first times that I’m aware of that a research group has targeted a subset and dug deeper into it. Scheibenbogen’s focus is clearly good news for people in that subset but it’s also good news for people outside of it. If she’s found a robust subset then it needs to be peeled off from other ME/CFS patients because it’s undoubtedly confounding study results for those patients.

2017 Award

The 2017 Ramsay Award will determine if T-cells and monocytes are up to the task in ME/CFS. We know that NK and probably T-cells are laggards in ME/CFS patients’ immune systems, but other immune cells are largely untested.

Following on recent findings of impairments in energy production, the Scheibenbogen group is going to determine if T-cells and monocytes have the energy to spring into action when needed. Immune cells are mostly quiescent until they come across a pathogen, at which point they’re required to rev up their engines and explode into action. If they don’t have the energy to “explode” they’ll have difficulty fighting off bugs.

If I have it right, they’re also going to stimulate cells using adrenergic and acetylcholinergic factors to see if they affect their metabolism or energy production. Given the role these factors appear to play in the deranged stress response found in ME/CFS, finding a metabolic tie-in would be exciting indeed.

Simmaron Scheibenbogen Collaboration Underway

The Simmaron Research Foundation is also working with Dr. Scheibenbogen to identify the subset of Dr. Peterson’s patients who fit the autoimmune profile, and to further characterize the subset from a clinical perspective.

A Leader

Over the past five years Scheibenbogen has become deeply immersed in ME/CFS. She was the lead author of a paper on the EUROMENE network, which contains researchers and clinicians from 17 European countries. Euromene was accepted into the COST (Cooperation in Science and Technology) framework which was established by the European Union to support collaboration in scientific endeavors. While COST does not fund research studies, it does fund networks and provides networking possibilities across the European Union.

EUROMENE members

One goal of Euromene COST Action is to establish a “sustainable integrated network of researchers in Europe working in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and to promote cooperation between research groups.

Coordination and collaboration appears to be becoming a bigger and bigger theme. The OMF and the SMCI held collaborative and networking meetings last year. The NIH research centers are collaborating on one large project. Canada’s May Montreal conference is focusing on establishing cooperative efforts to understand ME/CFS. (Dr. Scheibenbogen will be attending.) The OMF’s next conference is set for September of this year.

However Dr. Scheibenbogen got interested in ME/CFS, it’s great to see her get so involved so quickly. She reminds me of another relatively new researcher in the field – Dr. Maureen Hanson – who quickly cranked out research studies and is now leading an NIH ME/CFS research center. It’s good to see new researchers have success in this field.

Of course, the going is still tough. In an SMCI interview Dr. Scheibenbogen seemed astonished at the lack of opportunities for research into what she described as a frequent and severe disease.

But still the situation is very disappointing with so little support for patients and research and almost no interest from pharmaceutical companies to perform clinical studies. I am a trained oncologist and hematologist and there the situation is so different with so much research and drug development.

Like everyone else in this field, Dr. Scheibenbogen is a pioneer and pioneers by definition have rough going. Like the pioneers of old she’s forging a path through some hostile territory, not as the pioneers did in the old West but this time German medical circles. Her work is getting results, though, results that her colleagues will surely notice. Here’s to a new presence in the field who’s put, perhaps for the first time, Germany – the most powerful nation in Europe – on the ME/CFS map.

Why should a blog focused on chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) be interested in multiple sclerosis? Because some distinct similarities exist between the three diseases, and when diseases like ME/CFS and FM aren’t getting much research, sometimes it pays to pay attention to diseases that are. You never know what insights might open up.

A recent study indicated that ME/CFS was more functionally disabling than multiple sclerosis

For the record, while multiple sclerosis is not as disabling as ME/CFS (yes – studies indicate that ME/CFS is more disabling than MS), MS is considered one of the most fatiguing diseases known. (Dr. Light’s study actually found more fatigue in MS but much less post-exertional malaise ME/CFS.)

Additionally, MS like ME/CFS and FM, mostly strikes women in mid-life. Plus, having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and one suspects, FM as well. Infections often trigger relapses in both MS and ME/CFS. Pregnancy also often brings a respite for women with either MS or ME/CFS (often unfortunately followed by a relapse.) Central nervous system involvement is present in all three diseases. In fact, Simmaron’s spinal fluid study found similar levels of immune dysregulation in ME/CFS and multiple sclerosis.

A new MS study highlights a vital aspect of medical research – an animal model – that both chronic fatigue syndrome and fibromyalgia lack. It illuminates how researchers can use animal models to crack complex medical mysteries. Tantalizing leads are present in both FM and ME/CFS but no one has been able to meld them into a bonafide breakthrough. That appears to have happened in MS.

Let’s see what happens in a well-studied, well-funded disease. As a bonus we’ll see that the hopeful breakthrough in MS could even have relevance to ME/CFS and FM.

One of the huge questions facing ME/CFS, fibromyalgia, MS and many autoimmune diseases is why so many more women than men get ill. Women don’t just get more autoimmune diseases, they tend to get them earlier than men and tend to have more severe cases. No one knows why but researchers have been scratching around a possible answer for at least a decade.

A Serendipitous Mistake Sparks a Major Finding

A mistake in differentiating male from female mice led to a major discovery.

As so often happens in research, a serendipitous mistake sparked this discovery. It began when a Northwestern University graduate student accidentally used a male mouse instead of a female mouse in an experiment. (Female mice are apparently hard to distinguish from male mice.) The researchers were using female mice to find genetic mutations that could help prevent the progression of MS – a female dominated disease.

When they ran the experiment they found, to their great surprise, that the genetic mutation that was protective in female mice actually made things worse for the male mice. (Talk about a gender divide.) Digging deeper, the team found that the genetic mutation in male mice blocked the activity of immune cells (ILC2) that are protective against multiple sclerosis in female mice. These cells halt the production of TH17 T-cells that initiate the attack on the myelin sheaths of neurons in MS.

Mast Cells Make Good

Mast cells are usually associated with allergic responses and in ME/CFS/FM with a condition called mast cell activation syndrome (MCAS) but this study revealed that mast cells can have a protective side as well.

Testosterone

A male hormone, testosterone, then reared its head. In men testosterone triggers mast cells to produce a substance called IL-33 which stops the production of the TH17 cells in their tracks. In fact, when the Northwestern University researchers removed the mast cells from the male mice their neurons came under attack and they developed mouse MS. In the presence of testosterone, then, mast cells are a very nice thing to have.

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

Female mice, which have seven to eight times less testosterone than male mice, don’t produce enough testosterone to induce their mast cells to produce IL-33. Instead, female mast cells produce cytokines which increase inflammation and the TH17 T-cells that have been fingered in MS.

Testosterone has been on MS researchers’ radar for quite some time. A recent review of hormonal related changes in MS asserted that there is “compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system”.

Testosterone levels that drop as men age track with an increased incidence of MS in later life. (Interestingly the men who do get MS tend to have a tougher time with it than women.) Lower testosterone levels in men with multiple sclerosis are also associated with greater disability. Some similar findings have been found in women. Women with MS tend to have lower testosterone levels, and increased lesions were associated with reduced testosterone levels in one study.

A very small clinical trial suggested testosterone supplementation might be able to increase white matter volume in the brains of men with MS. If that finding is validated in larger studies, testosterone might be the first substance found that can reverse some of nervous system damage found in MS.

Testosterone, ME/CFS and FM

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

A few studies have implicated testosterone in two other gender-imbalanced diseases – chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

Two studies have found low levels of testosterone in fibromyalgia, and testosterone levels have strongly been linked to pain sensitivity in animal models. One recent study suggested that lower levels of testosterone in combination with other factors was associated with increased rates of depression and poorer sexual functioning in FM. Recently, Jarred Younger’s small “good-day, bad-day” FM study found that lower levels of two hormones, testosterone and progesterone, were associated with more severe FM symptoms.

Despite concerns about the use of testosterone in women, White found that a 28 day course of testosterone gel reduced pain significantly in women with FM. (More about that later.)

In ME/CFS Broderick’s modeling efforts suggest that testosterone in men is protective. Plus the high rate of gynecological issues in ME/CFS and fibromyalgia suggest that sex hormones are involved in ME/CFS.

Testosterone and Autoimmunity

No one knows if ME/CFS and FM are autoimmune diseases, but both could be and the link could have something to do with testosterone. The evidence that testosterone is protective against some autoimmune diseases is building.

Adding the gut contents of male mice to female mice (another mouse model) reduced their risk of type I diabetes – an autoimmune disease. Interestingly, the protective element again appeared to be testosterone, the levels of which were highly influenced by the composition of the mice gut flora.

Declining testosterone levels in men as they age increases their risk for rheumatoid arthritis. Declining testosterone levels may also be responsible for the gender parity seen in RA by age 75, and could explain why men tend to get multiple sclerosis at a later age than women. Low androgen levels in both men and women also appear to put them at risk for autoimmune disorders.

A TH17 Connection

ME/CFS may share another connection with multiple sclerosis – a deranged TH17 response. TH17 T-cells defend against extracellular pathogens and have been found to play a significant role in the development of inflammatory and autoimmune disorders. TH17 cells appear to help initiate attack on the neuronal sheaths in MS.

Several studies from Dr. Klimas’s group suggest a TH17 associated process may be in play in ME/CFS. Exercise provoked a Th17 response in both ME/CFS and Gulf War Syndrome patients. Broderick’s modeling effort found that as few as five cytokines associated with TH17 activation could identify approximately 80% of ME/CFS patients with an infectious trigger. TH17 cytokines showed up again prominently in Broderick’s network analysis study which found they functioned as “preprogrammed immune component”.

Treatment

The question now is how induce a testosterone-like response in women without actually using testosterone. Drug studies suggest that testosterone can be helpful in MS but the study authors stated that women can’t take much of it without becoming masculinized and experiencing other significant side effects.

Instead this new MS study’s importance lies in the discovery of a key cytokine (IL-33) that can apparently turn off the destructive nerve processes in MS and even restore the nerves. If researchers can develop a way to promote IL-33 activity without using testosterone in women, they may have gotten a handle not just on MS but possibly on other gender imbalanced autoimmune diseases as well.

A New Approach to Autoimmunity?

The authors were quick to suggest that the findings may apply to other autoimmune diseases as well and could ultimately signal an entirely new approach to them. That’s welcome news given the harsh side effects of many of the immune suppressants used in autoimmune diseases.

“This suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females. These findings could lead to an entirely new kind of therapy for MS, which we greatly need.” Melissa Brown, PhD.